Managing argatroban in heparin‐induced thrombocytopenia: A retrospective analysis of 729 treatment days in 32 patients with confirmed heparin‐induced thrombocytopenia

Abstract

Argatroban is a first-line anticoagulant for patients with heparin-induced thrombocytopenia (HIT). Published data on practical aspects of its use in HIT are lacking. We aim to establish recommendations based on our experience. This cohort of 32 patients is the largest describing cases of HIT confirmed by a functional assay treated with argatroban. Among patients with normal liver function, median starting argatroban doses (SAD) of 0.54, 0.98, and 1.27 μg/kg/min reached steady-state plasmatic argatroban concentrations (PAC) of 0–0.39, 0.40–0.99, and 1.00–1.5 μg/ml, respectively. Median argatroban dose increases (ADI) induced similar median steady-state PAC increases (Δ μg/kg/min ≈ Δ μg/ml). PAC measurements performed more than 240 min after SAD or ADI were significantly higher compared to earlier controls. Quantitative PAC measurements and thrombin time (TT) appeared adequate for monitoring. Thirty-eight percent of the thrombotic events were preceded by PAC below 0.4 μg/ml. Four hours after argatroban discontinuation, median international normalised ratio (INR) decrease was −1.2. We suggest: (i) monitoring argatroban with PAC or TT at least 240 min after SAD and/or AID; (ii) using SAD of 1.0 μg/kg/min and ADI of at least 0.2 μg/kg/min when liver function is normal; (iii) targeting therapeutic PAC of 0.5–1.0 μg/ml; and (iv) targeting INR of 3.5–4.5 when bridging argatroban with vitamin K antagonists. Heparin-induced thrombocytopenia (HIT) is an adverse effect of unfractionated (UFH) and low-molecular-weight heparin (LMWH), occurring with variable risk depending on the type and dose of heparin and the clinical context.1-4 HIT is characterised by a severe limb- and life-threatening pro-thrombotic state requiring immediate cessation of all heparin and a switch to an alternative non-heparin anticoagulant.5-9 Argatroban is an effective first-line therapy for HIT5, 10 and was described in a recent meta-analysis as being superior to other parenteral drugs used for the management of HIT.11 Argatroban is a synthetic, reversible and competitive direct thrombin inhibitor, which binds thrombin on its catalytic site12 and is hepatically metabolised.13 Less is known, however, about several practical aspects of anticoagulation with argatroban. The magnitude of starting doses and dose adaptations, as well as the degree of dose reduction required among patients with different types of hepatic dysfunction remain unclear and are performed empirically. Furthermore, despite recent guidelines,10 the best timing of, and laboratory assays for, argatroban monitoring still remain open to discussion. The aim of our study was to investigate how argatroban therapy is conducted at our institution and to develop evidence-based in-house recommendations for an optimal anticoagulation with argatroban in patients with HIT. This was a retrospective observational derivation study. Data were collected between October 2018 and February 2019 and analysed between February 2019 and August 2021. Between August 2014 and February 2019, 32 patients with confirmed HIT14 [positive anti-PF4/heparin antibodies by HemosIL-Acustar-HIT-IgG (Instrumentation Laboratory GmbH, Munich, Germany) (a chemiluminescent immunoassay, CLIA) and ID-H/PF4-PaGIA (Bio-Rad, DiaMed SA, Basel, Switzerland) (a particle gel immunoassay, PaGIA) and positive heparin-induced platelet aggregation (HIPA, University Hospital, Greifswald, Germany)] received argatroban at our institution and were included in this study. We performed the following assays on an automated coagulometer (Sysmex CS-5100; Siemens Healthineers, Erlangen, Germany): (i) activated partial thromboplastin time (aPTT; Pathromtin SL®; Siemens Healthineers, Erlangen, Germany); (ii) thrombin time (TT; Thromboclotin®, Siemens Healthineers, Erlangen, Germany) with a final thrombin concentration of 1.25 U/ml; and (iii) assessment of the plasma argatroban concentration by a commercial diluted TT assay (Hemoclot Thrombin Inhibitors; Hyphen Biomed, Neuville-sur-Oise, France). As argatroban is mainly metabolised in the liver, we divided the studied patients into four categories according to their estimated liver function. (i) Normal liver function: serum alanine aminotransferase (ALT) levels less than 180 U/l [three times the upper limit of normal (ULN)] and serum total bilirubin levels less than 25.5 μmol/l.13 When a patient previously had ALT higher than 180 U/l and/or serum total bilirubin higher than 25.5 μmol/l and recovered, he was included into the ‘normal liver function group’ five days after recovery of ALT less than 180 U/l and serum total bilirubin less than 25.5 μmol/l. (ii) Liver cytolysis: ALT higher than 180 U/l and serum total bilirubin less than 25.5 μmol/l. (iii) Impaired bilirubin excretion: ALT less than 180 U/l and serum total bilirubin higher than 25.5 μmol/l. (iv) Liver cytolysis associated with impaired bilirubin excretion: ALT higher than 180 U/l and serum total bilirubin higher than 25.5 μmol/l. Median and interquartile range (IQR) values were calculated with Excel (Microsoft Schweiz GmbH, Zürich-Flughafen, Switzerland). We employed MedCalc (version 15.11.0; MedCalc Software Ltd, Ostend, Belgium) to perform Passing–Bablock regression analysis. Sigma Plot (version 13.0; Systat Software GmbH, Erkrath, Germany) was used to create Figure 1 and GraphPad Prism (version 8; GraphPad Software, San Diego, USA) was used to create Figures 2-8 and to perform Mann–Whitney tests (t-test, unpaired values, non-parametric distribution), Wilcoxon tests (t-test, paired values, non-parametric distribution) and Spearmann correlation measures. The study complies with the guidelines of the Institutional Ethical Board (Commission Cantonale Vaudoise d'Ethique de la Recherche sur l'Être Humain, CER-VD, protocol number 497/95) and was accepted for quality control assessment of laboratory and clinical management practice. Thirty-two patients with confirmed HIT (15 of them presenting with HIT and thrombosis, HIT-T) were treated with argatroban. Twenty-seven patients (84%) only received argatroban and five (16%) received multiple treatments (Table 1). Overall, we studied 729 argatroban treatment days. Median duration of argatroban therapy was 17.5 days (IQR 10–29.5). Compared to the cohort published by Tardy-Poncet et al.,15 we registered a higher rate of death related to HIT (n = 1/32 vs. 0/16), a similar rate of thromboembolic complications (n = 13/32, 41% vs. n = 7/16, 44%), and less major bleeding (n = 4/32, 13% vs. n = 3/16, 19%) and overall death rates (n = 4/32, 13% vs. n = 4/16, 25%). Individual clinical courses are detailed in Table 2. Argatroban; 11 days Central venous catheter (jugular) already removed at time of HIT diagnosis 1: Left lower limb Gritti amputation 13 days after HIT diagnosis 2: Right heel necrosectomy 43 days after HIT diagnosis 3: Left fingers 2,3,4,5 amputations 50 days after HIT diagnosis 4: Right fingers 2,3,4 amputation and right foot toes 1,3,4,5 amputation 104 days after HIT diagnosis NB: patient suffered acute hepatic necrosis and ischaemic limb necrosis before onset of HIT Cava filter on day −5 of treatment argatroban; 24 days Argatroban; 21 days Left lower limb prothetic bypass between superficial femoral artery and popliteal artery YES* 1 major bleeding; hematochezia (argatroban; ASS cardio and clopidogrel 1 minor bleeding; melena (argatroban and clopidogtrel) Argatroban; 21 days median laparotomy; resection of 1.5 m of bowel YES* Intra-ventricular thrombus (already present before HIT) with multiples embolic strokes; thrombo-emboly into the anterior Interventricular coronary artery We observed 13 thromboembolic events among nine different patients (Table 3). Seven were venous and six were arterial thromboses. Five out of 13 (38%) thromboembolic events were related to an anticoagulation that was probably inadequate. Indeed, PAC had been below 0.4 μg/ml in the 24 h preceding diagnosis in four cases and three days before diagnosis in one patient. Additionally, other risk factors were present: recent surgery and immobilisation (n = 11), systemic infection (n = 8), active cancer (n = 6), body mass index (BMI) higher than 30 kg/m2 (n = 2), intravascular devices (n = 5), and/or poor haemodynamic conditions (n = 4). Concerning the five bleeding events (Table 4), four were considered as major according to the International Society for Thrombosis and Haemostasis (ISTH) definitions.16, 17 PAC measured in the 24 h preceding these bleeding events were within target ranges in 4/5 patients. Among the major bleeding events, two intracranial haemorrages occurred after ischaemic strokes and were considered as secondary to anatomical brain lesions. The other two major bleeding events occurred under concomitant double antiplatelet therapy. Vesical, prostatic and ureteral lesions secondary to self-removal of urinary catheter; internal jugular vein lesion secondary to self-snatch of central venous catheter clopidogrel and aspirin treatments (recent stenting of RIVA); renal impairment; reduced haemoglobin 2 units of packed red blood cells Mean: 0.39 (0; 0.41; 0.61; 0.52) Clopidogrel and aspirin treatments; reduced haemoglobin due to digestive angiodysplasia Ischaemic colitis 5 UPN: 15.186 Four (13%) patients underwent limb amputation and four patients died (Table 2). Among patients that underwent amputation, three had established advanced peripheral arterial disease. The fourth patient suffered acute hepatic necrosis with ischaemic limb necrosis18 prior to HIT onset and underwent amputation during argatroban therapy (unique patient number, UPN 15.103). Among the four deceased patients, three were still under argatroban therapy at the time of death. In one patient (UPN 16.193), death was directly related to HIT. In two cases, advanced comorbidities may have contributed to the fatal outcome (UPN 18.148 and UPN 15.001). As depicted in Figure 1, we recorded a median platelet count nadir of 51 G/l on the second day of argatroban therapy, which was followed by full recovery (>150 G/l) on the seventh to eighth day of treatment. In parallel, median D-dimers levels progressively decreased. Every starting argatroban dose (SAD, μg/kg/min) and the corresponding PAC measurements (μg/ml) at time t′ (min) after SAD were analysed. Among patients with normal liver function, we divided all recorded SAD into two categories, according to an intended SAD of 0.5 or 1.0 μg/kg/min, respectively. As illustrated in Figure 2A, after an overall median SAD of 0.5 μg/kg/min (IQR 0.48–0.58), median PAC among controls performed within 240 min reached 0.26 μg/ml (IQR 0.20–0.35) vs. 0.44 μg/ml (IQR 0.29–0.53) in controls at least 240 min after argatroban initiation (p-value = 0.0275). Of note, median SAD administered in patients with monitoring performed after at least 240 min (0.53 μg/kg/min) did not differ significantly from SAD applied in controls less than 240 min (0.50 μg/kg/min; p-value = 0.1594). Figure 2B shows data for an intended SAD of 1 μg/kg/min (median, 1.04, IQR 0.94–1.09). This led to median PAC of 0.30 μg/ml (IQR 0.14–0.63) among controls less than 240 min versus 0.77 μg/ml (IQR 0.74–0.97) in controls at least 240 min after argatroban initiation, respectively (p-value = 0.0749). Again, median SAD administered in patients with monitoring after at least 240 min (0.98 μg/kg/min) did not significantly differ from SAD applied in controls after less than 240 min (1.06 μg/kg/min, p-value >0.9999). The most frequent dose adaptations in our cohort were ADI motivated by clinico-biological features, such as monitoring parameters below target ranges, insufficient improvement of platelet count and/or D-dimers, and thromboembolic events. Among patients with normal liver function, recorded ADI were divided into four intervals (+0.01–0.10, 0.11–0.20, 0.21–0.30, and 0.31–0.40 μg/kg/min). Figure 3A depicts PAC measured 3–6 h after ADI (median: 240 min, IQR: 217–297), showing that median PAC increases (μg/ml) corresponded roughly to the respective ADI (μg/kg/min). Among patients with normal liver function, ADI within a magnitude of 0.11–0.40 μg/kg/min were divided into two groups, based on the timing of monitoring: within 3 h (median, 128 min) or between 3 and 6 h (median, 240 min) after ADI. Figure 3B shows that late monitoring was associated with significantly higher PAC compared to early monitoring, despite the fact that, paradoxically, the median ADI performed in the group with PAC control within 3 h was significantly higher compared to the group with PAC control performed after 3–6 h (median, 0.22 vs. 0.21 μg/kg/min, IQR 0.21–0.26 vs. 0.14–0.22, p-value = 0.048). Steady-state PAC was defined as no argatroban dose modification in the 6 h preceding monitoring. Patients were divided into four categories according to their estimated liver function. For each group, we created PAC intervals according to the treatment aim: (i) ‘prophylactic’ PAC, 0–0.39 μg/ml (Figure 4A); (ii) ‘standard therapeutic’ PAC, 0.40–0.99 μg/ml (Figure 4B); and (iii) ‘high therapeutic’ PAC, 1.00–1.5 μg/ml (Figure 4C). At steady state, patients with normal liver function required median (IQR) argatroban doses of 0.54 μg/kg/min (0.47–1.0), 0.98 μg/kg/min (0.61–1.32), and 1.27 μg/kg/min (0.90–1.45) to reach prophylactic, standard therapeutic, or high therapeutic PAC, respectively. Patients with liver cytolysis required argatroban doses of 0.25 μg/kg/min (0.24–0.29), 0.78 μg/kg/min (0.53–1.10), and 1.08 μg/kg/min (0.69–1.08) respectively, and patients with hyperbilirubinaemia, argatroban doses of 0.12 μg/kg/min (0.11–0.16), 0.16 μg/kg/min (0.12–0.18), and 0.51 μg/kg/min (0.10–0.51). Median argatroban doses were significantly lower in patients with hyperbilirubinaemia compared to patients with normal liver function or liver cytolysis and this was irrespective of the PAC interval. Moreover, among patients with liver cytolysis, median argatroban doses were significantly lower compared to those in patients with normal liver function in the ‘prophylactic’ and ‘high therapeutic’ PAC intervals. Figure 5 depicts argatroban doses at steady state and concomitant bilirubin level, according to the targeted PAC. Among patients that had ‘prophylactic’ (0–0.39 μg/ml; Figure 5A) and ‘standard therapeutic’ (0.40–0.99 μg/ml; Figure 5B) PAC, serum total bilirubin levels and argatroban doses at steady state were strongly inversely correlated [Spearmann r (95% confidence interval (CI)): −0.8203 (−0.9156; −0.6376), p-value: <0.0001, n = 28 pairs and −0.8728 (−0.9185; −0.8041), p-value: <0.0001, n = 77 pairs, respectively]. Inverse correlation was lower among patients that had a ‘high therapeutic’ (≥1.0 μg/ml; Figure 5C) PAC [Spearmann r (95% CI): −0.5334 (−0.7644; −0.1809), approximate p-value: 0.0042, n = 27 pairs]. Three different assays for argatroban anticoagulation monitoring were available: aPTT (s), TT (s), and PAC (μg/ml). PAC and corresponding simultaneous TT and aPTT were analysed. PAC and corresponding single TT values showed the highest Spearman correlation [ρ (95% CI): 0.726 (0.689–0.7599); n = 749 pairs], while aPTT and simultaneous PAC showed a lower correlation [ρ (95% CI): 0.590 (0.548–0.630); n = 1031 pairs]. As shown in Figure 6A, increasing TT intervals showed a linear trend, with 80% of TT values higher than 79 at least a therapeutic PAC μg/ml). Of note, while aPTT intervals within showed a linear with the corresponding PAC, aPTT intervals higher than (Figure PAC was after argatroban in of bleeding events, and to vitamin K PAC at time t′ after argatroban were calculated as of the steady-state concentration and with a We that argatroban had an approximate plasma of min among patients with normal hepatic function (Figure of data we not PAC after argatroban among patients with Figure depicts median international ratio (INR) among patients (n = treated with and argatroban. Median INR was before argatroban and measured 6 h (median, min) following argatroban INR decrease IQR INR decrease to In to develop evidence-based in-house recommendations for argatroban and monitoring we analysed a cohort of 32 patients with confirmed about of them (n = presenting with (Table 1). Median anticoagulation duration was 17.5 days (IQR range for a total of 729 treatment days. As depicted in Figure 1, argatroban was decrease of D-dimers and platelet count within days of a of haemoglobin are in with those in our not the of the laboratory control 2 h after starting Among patients with normal liver function, a steady-state plasmatic concentration is reached at the h after starting in of a SAD of 0.5 μg/kg/min (Figure and 1.0 μg/kg/min (Figure on our we a plasmatic argatroban of 1 h (Figure which with published are in with those of Tardy-Poncet et that argatroban concentrations measured 2 h after SAD were lower than steady-state concentrations 0.39 μg/ml vs. μg/ml on these and four to five are to reach plasma steady state after starting we the PAC control at least h after our is only one that the magnitude of argatroban dose adaptations and their on guidelines on management of patients with HIT did not recommendations on this data (i) ADI intervals of 0.11–0.20, 0.21–0.30, and μg/kg/min to PAC increases (Figure (ii) a ADI induced a roughly similar median PAC Δ ADI μg/kg/min ≈ Δ PAC and (iii) in PAC increases were observed between ADI of μg/kg/min and μg/kg/min and between ADI of μg/kg/min and 0.31–0.40 timing of laboratory monitoring is for a to the best of our are no published data this practical to we have observed with monitoring (Figure 2), we in Figure 3B that after ADI of μg/kg/min, median PAC was significantly when laboratory control was performed 3 to to 6 compared to controls 3 this that timing of control after argatroban dose is and we h after dose among patients with normal liver function. The argatroban dose required to reach a target PAC on liver function. As by et serum total bilirubin more than ALT to patients dose on the of bilirubin and/or we defined four different hepatic (Figure 4). Patients with bilirubin levels required significantly lower argatroban steady-state doses than patients with normal liver function irrespective of the target PAC interval. Patients with liver cytolysis to lower median argatroban doses at steady state than patients with normal liver function, in to reach and high therapeutic PAC intervals. data that impaired bilirubin the most in for argatroban and that patients with liver cytolysis probably argatroban dose compared to patients with impaired bilirubin total plasma bilirubin higher than 25.5 μmol/l been to patients with impaired bilirubin requiring argatroban dose as in Figure we not a serum total bilirubin a on the required in to a (Figure standard therapeutic (Figure or high therapeutic PAC (Figure 5C) already at bilirubin values within on our we to argatroban doses among patients with serum total bilirubin levels which is lower than the by et partial thromboplastin time is the most laboratory assay for monitoring argatroban anticoagulation and is by the Society of multiple factors its to monitoring, which in may in argatroban and group and have shown that TT is more and for the monitoring of Figure a linear between PAC and corresponding TT intervals. In the between increasing PAC and simultaneous aPTT intervals is not a for aPTT values (Figure that this assay is less for monitoring argatroban We to argatroban by TT when the assessment of PAC with a diluted TT assay is not an of to two with final thrombin concentrations of 1.5 and 5 as we did in our 24 our that a single TT with a final thrombin concentration of 1.25 is adequate to argatroban concentrations of about 1 μg/ml (Figure argatroban with assays is in with We an argatroban plasma of about 1 h in patients with normal liver function (Figure Figure that the of PAC after argatroban the We argatroban at least 2 h before among patients with normal liver function. As well as direct are still employed for HIT patients after the acute targeting INR values between 2 and 3 for optimal Of note, argatroban and other direct thrombin INR this that during the of anticoagulation with argatroban and INR values than have to before et to target INR values higher than and et INR controls 6 h after argatroban In Figure we that INR values from to during the are to a target INR of after argatroban Indeed, we observed a median INR decrease of when control was performed 3–6 h after argatroban data are in with those by two other observed median INR of 28 study this was a study. our data were collected argatroban monitoring with a commercial diluted TT is not all HIT cases were confirmed by a functional standard we studied patients treated in a clinical and analysed an argatroban treatment of 729 days. Moreover, to the best of our our cohort is the described patients with HIT confirmed by a functional standard assay were treated with on practical aspects of anticoagulation of HIT patients with such (i) the effect of argatroban starting doses and dose on the following plasma (ii) the effect of liver function on argatroban (iii) the effect of timing and laboratory assay on and (iv) the effect of therapeutic argatroban on INR on these data we have a in-house management protocol (Table 5), which we are we not between HIT and and a SAD of 1.0 μg/kg/min in all HIT patients with normal liver function. In patients with impaired liver function, we decrease SAD to μg/kg/min in of hepatic cytolysis and to 0.25 μg/kg/min in of We treatment with a double and one we PAC at steady state a which is more than the other we the of platelet and levels in to the anticoagulation required in each patient. and values, not and values, not and values, not and values, not We the for the patients, the of the for and for as of the of This study been at the and in by de on after been The not have of to the collected and analysed and the the and the and collected the was in of the patients, analysed data and the is the corresponding of the was in of the patients, the analysed and the and the final of the The is not for the or of by the than to the corresponding for the

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